The goal of this project has been to examine the central effects of changes in reproductive endocrine function occurring in the context of hypogonadism. Investigations have been primarily focused on the characterization of affective disorders occurring during the perimenopause and midlife, the identification of the role of gonadal steroids in these mood disorders, and the examination of the neuroregulatory consequences of the presence and absence of gonadal steroids. Finally, the information obtained by these protocols will help identify the predictive utility of endocrine measures in perimenopausal depression and help define the role of hormonal therapies in mood disorders occurring at midlife in men and women. Findings to date: 1) a significant improvement in depression severity scores and libido (but not measures of cognitive function) after DHEA administration was seen in 23 men and 23 women with midlife-related depression; 2) DHEA increased plasma levels of free testosterone (Free T) in both men and women; 3) neither gender nor plasma hormone levels predicted therapeutic response to DHEA administration in midlife-related depression; 4) the maintenance of antidepressant effectiveness and preliminary evidence of an increase in bone density (as measured by DEXA scan) was documented in nine subjects who have received DHEA for one year; 5) seven of 10 depressed perimenopausal women have experienced a remission of their depression during participation in a double-blind placebo-controlled trial of estradiol, phytoestrogens, and SERMs; and 6) the SERM raloxifene was associated with an increase in plasma estradiol levels and a remission of mood symptoms in three (of three) perimenopausal depressed women. In a study involving the induction of hypogonadism in women with GnRH agonists, we have observed the hypogonadal state to be associated with elimination in women of both cognition activated regional cerebral blood flow (O15 3D PET scans) in the dorsolateral prefrontal cortex and the reciprocal functional connectivity between the left hippocampal formation and the contralateral dorsolateral prefrontal cortex compared to either estradiol or progesterone replacement. Finally, in collaboration with NICHD we have observed that women with Turner Syndrome (n = 100) have significantly higher scores on measures of shyness (but not depression or anxiety) than either asymptomatic controls (n = 35) or women with premature ovarian failure (POF) (n =100), and women with POF have an increased frequency of past episodes of depression compared to community samples of women.